Abemaciclib

Registered South African indications:

• Early breast cancer
  - In combination with endocrine therapy for adjuvant treatment of adult patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−), node-positive early breast cancer at high risk of recurrence. In pre- or perimenopausal women, aromatase inhibitor endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist
• Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) advanced or metastatic breast cancer
  - In combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women; and men, with hormone receptor (HR+), human epidermal growth factor receptor 2 negative (HER2−) advanced or metastatic breast cancer
  - In combination with fulvestrant for adult patients with disease progression following endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist
  - As monotherapy for adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting

Contraindications

South African recommendations

• Hypersensitivity to abemaciclib or any of the ingredients
• Pregnancy
• Breastfeeding
• Coadministration with ketoconazole

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

South African recommendations

• Severe renal impairment
  - End-stage renal disease
  - Patients on dialysis
• Severe hepatic impairment (Child-Pugh Class C)
• Grade 3 or 4 diarrhoea
• Grade 3 or 4 neutropenia
• Persistent or recurrent Grade 2 interstitial lung disease/ pneumonitis
• Alanine aminotransferase (ALT) elevation
• Galactose intolerance, e.g. galactosaemia
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• Fructose intolerance
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Severe renal impairment
  - End-stage renal disease
  - Patients on dialysis
• Severe hepatic impairment (Child-Pugh Class C)
• Grade 3 or 4 neutropenia
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation
• ≥Grade 2 diarrhoea
• Interstitial lung disease/ pneumonitis
  - Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1
  - Grade 3 or 4
• Visceral crisis
• Coadministration with CYP3A4 inducers
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery 

Forms avail. in SA and covered in this monograph: fct

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Early breast cancer
- In combination with endocrine therapy for adjuvant treatment of adult patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−), node-positive early breast cancer at high risk of recurrence. In pre- or perimenopausal women, aromatase inhibitor endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist

• Oral (fct): 150mg, twice daily with or without food; Treatment duration: Continuously for two years, or until disease recurrence or unacceptable toxicity occurs

Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) advanced or metastatic breast cancer
- In combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women; and men, with hormone receptor (HR+), human epidermal growth factor receptor 2 negative (HER2−) advanced or metastatic breast cancer
- In combination with fulvestrant for adult patients with disease progression following endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist

• Oral (fct): 150mg, twice daily with or without food; Treatment duration: Continuously as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs

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When used in combination with fulvestrant, tamoxifen or an aromatase inhibitor, refer to the full professional information of the individual adjuvant medicines for the recommended doses

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Pre/perimenopausal women and men treated with the combination of abemaciclib plus an aromatase inhibitor should be treated with a gonadotropin-releasing hormone (GnRH) agonist according to current clinical practice standards
Pre/perimenopausal women treated with the combination of abemaciclib plus fulvestrant should be treated with a gonadotropin-releasing hormone (GnRH) agonist according to current clinical practice standards

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- As monotherapy for adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting

• Oral (fct): 200mg, twice daily with or without food; Treatment duration: Continuously as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs

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If the patient vomits or misses a dose of abemaciclib, instruct the patient to take the next dose at its scheduled time. Instruct patients to swallow abemaciclib tablets whole and not to chew, crush, or split tablets before swallowing. Instruct patients not to ingest abemaciclib tablets if broken, cracked, or otherwise not intact

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See additional prescribing points for dose modification guidance for some adverse events that may require dose interruption and/or dose reduction

Not established for use in children and adolescents below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Abemaciclib is contraindicated during pregnancy
• Based on findings in animals, abemaciclib can cause foetal harm when administered to a pregnant woman
• In animal studies, abemaciclib was teratogenic and caused decreased foetal weight at maternal exposures that were similar to human clinical exposure based on AUC at the recommended human dose. Advise pregnant women of the potential risk to a foetus
• Women with reproductive potential should have a negative pregnancy test before starting abemaciclib. They should use highly effective contraception during treatment and for 3 weeks after the last dose of abemaciclib

Recommendations in other jurisdictions

• Caution; not recommended
• There are no data from the use of abemaciclib in pregnant women. Studies in animals have shown reproductive toxicity. Abemaciclib is not recommended during pregnancy and in women of child-bearing potential not using contraception
• Women of childbearing potential should use highly effective contraception methods (e.g. double-barrier contraception) during treatment and for at least 3 weeks after completing therapy

Breastfeeding

South African recommendations

• Contraindicated
• Women taking abemaciclib should not breastfeed their infants
• Because of the potential for serious adverse events in breastfeeding infants from abemaciclib, a breastfeeding woman should not breastfeed during treatment with abemaciclib and for at least 3 weeks after the last dose

Recommendations in other jurisdictions

• Caution; not recommended
• It is unknown whether abemaciclib is excreted in human milk. A risk to newborns/ infants cannot be excluded. Patients receiving abemaciclib should not breastfeed

Fertility

South African recommendations

• Cytotoxic effects to the male reproductive tract in rats and dogs indicate that abemaciclib may impair fertility in males
• No effects on female reproductive organs were observed

Recommendations in other jurisdictions

• The effect of abemaciclib on fertility in humans is unknown. While in rats no effects on male fertility were noted, cytotoxic effects to the male reproductive tract in mice, rats, and dogs indicate that abemaciclib may impair fertility in males
• No adverse effects on female reproductive organs in mice, rats, or dogs, nor effects on female fertility and early embryonic development in rats were observed

Renal Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no information available
  There are no data regarding abemaciclib administration in patients with severe renal impairment, end-stage renal disease, or in patients on dialysis

Hepatic Impairment

• Mild to moderate (Child-Pugh Classes A & B): No dose adjustment recommended
• Severe (Child-Pugh Class C): Caution; dose adjustment recommended
  Oral (tab): 150mg, dly

Elderly

• No dose adjustment recommended

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Dysgeusia
• Dizziness
• Fatigue

Cardiovascular Disorders

• Venous thromboembolism/thromboembolic events
  - Deep vein thrombosis (DVT)
  - Pulmonary embolism
  - Cerebral venous sinus thrombosis
  - Subclavian vein thrombosis
  - Axillary vein thrombosis
  - DVT inferior vena cava
  - Pelvic venous thrombosis

Respiratory Disorders

• Interstitial lung disease (ILD)/ pneumonitis

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting

Hepatobiliary Disorders

• Increased alanine aminotransferase (ALT)
• Increased aspartate aminotransferase (AST)

Genitourinary Disorders

• Increased serum creatinine

Endocrine and Metabolic Disorders

• Decreased appetite

Musculoskeletal Disorders

• Muscular weakness

Skin and Subcutaneous Tissue Disorders

• Alopecia
• Pruritus
• Rash
• Dry skin

Immune, Blood and Lymphatic System Disorders

• Infections
• Neutropenia
  - Febrile neutropenia
• Leukopenia
• Anaemia
• Thrombocytopenia
• Lymphopenia
• Fever

Sensory Disorders

• Increased lacrimation  

• Strong CYP3A4 inhibitors (See additional prescribing points)
• Clarithromycin
• Itraconazole
• Ketoconazole
• Lopinavir/ ritonavir
• Posaconazole
• Voriconazole
• CYP3A4 inducer
• Rifampicin
• Carbamazepine
• Phenytoin
• Renal transporters organic cation transporter 2 (OCT2) substrates
• Multidrug and extrusion toxin protein (MATE1), and MATE2-K substrates
• Dofetilide
• Creatinine
• P-glycoprotein (P-gp) substrates, particularly narrow therapeutic index substrates
• Breast cancer resistance protein (BCRP), particularly narrow therapeutic index substrates
• Digoxin
• Dabigatran etexilate
• Hormonal contraceptives

Other interactions

• Grapefruit or grapefruit juice
• St. John's wort

• Full blood count with differential
• Platelet count
• Hepatic function
  - Alanine aminotransferase (ALT)
  - Aspartate aminotransferase (AST)
  - Serum bilirubin
• Hepatitis B virus screening
  - Hepatitis B surface antigen (HBsAg)
  - Hepatitis B core antibody (anti-HBc)
  - Total Ig or IgG
  - Antibodies to hepatitis B surface antigen (anti-HBs)

Specific cases may require

• Pregnancy status

Additional observations

• Signs and symptoms of:
  - Infection
  - Deep vein thrombosis and pulmonary embolism
  - Diarrhoea/ dehydration
  - Interstitial lung disease/pneumonitis
• Monitor adherence

Management of adverse reactions that may require dose interruption and/or dose reduction

Dose adjustment recommendations for adverse reactions

Dose level	Abemaciclib dose - combination with fulvestrant, tamoxifen, or an aromatase inhibitor	Abemaciclib dose - for monotherapy
Recommended starting dose	150mg twice daily	200mg twice daily
First dose reduction	100mg twice daily	150mg twice daily
Second dose reduction	50mg twice daily	100mg twice daily
Third dose reduction	Not applicable	50mg twice daily

Management recommendations for haematologic toxicities^a

• Complete blood counts should be monitored prior to the start of therapy, every two weeks for the first two months, monthly for the next two months, and as clinically indicated

CTCAE* Grade	Management recommendations
Grade 1 or 2	No dose adjustment required
Grade 3	- Suspend dose until toxicity resolves to Grade 2 or less - Dose reduction is not required
Grade 3, recurrent; or Grade 4	- Suspend dose until toxicity resolves to Grade 2 or less - Resume at next lower dose
*CTCAE = Common terminology criteria for adverse events

• ^aIf blood cell growth factors are required, suspend abemaciclib dose for at least 48 hours after the last dose of blood cell growth factor and until toxicity resolves to ≤Grade 2
• Resume at next lower dose unless already performed for the toxicity that led to the use of the growth factor. Growth factor use as per current treatment guidelines

Management recommendations for diarrhoea

• At the first sign of loose stools, start treatment with antidiarrheal medicines and increase intake of oral fluids

CTCAE Grade	Management recommendations
Grade 1	No dose adjustment required
Grade 2	- If toxicity does not resolve within 24hrs to Grade 1 or less, suspend dose until resolution - Dose reduction is not required
Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures	- Suspend dose until toxicity resolves to Grade 1 or less - Resume at next lower dose
Grade 3 or 4 or requires hospitalisation

Management recommendations for hepatotoxicity 

• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and serum bilirubin should be monitored prior to the start of therapy, every two weeks for the first two months, monthly for the next two months, and as clinically indicated

CTCAE Grade for ALT and AST	Management recommendations
Grade 1 (>ULN-3.0 x ULN) Grade 2 (>3.0-5.0 x ULN), Without increase in total bilirubin above 2 x ULN	No dose adjustment required
Persistent or Recurrent Grade 2, or Grade 3 (>5.0-20.0 x ULN), Without increase in total bilirubin above 2 x ULN	- Suspend dose until toxicity resolves to baseline or Grade 1 - Resume at next lower dose
Elevation in AST and/or ALT >3 x ULN with total bilirubin >2 x ULN, in the absence of cholestasis	Discontinue abemaciclib
Grade 4 (>20.0 x ULN)	Discontinue abemaciclib
Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal

Management recommendations for interstitial lung disease (ILD)/pneumonitis

CTCAE Grade	Management recommendations
Grade 1 or 2	No dose adjustment required
Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	- Suspend dose until toxicity resolves to baseline or ≤Grade 1 - Resume at next lower dose
Grade 3 or 4	Discontinue abemaciclib

Management recommendations for venous thromboembolic events (VTEs)

CTCAE Grade	Management recommendations
Early breast cancer
Any grade	- Suspend dose and treat as clinically indicated - Resume abemaciclib when the patient is clinically stable
Advanced or metastatic breast cancer
Grade 1 or 2	No dose adjustment required
Grade 3 or 4	- Suspend dose and treat as clinically indicated - Resume abemaciclib when the patient is clinically stable

Management recommendations for other toxicities (excluding diarrhoea, haematologic toxicity, hepatotoxicity, venous thromboembolic events and ILD/pneumonitis)

CTCAE Grade	Management recommendations
Grade 1 or 2	No dose adjustment required
Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1	- Suspend dose until toxicity resolves to baseline or ≤Grade 1 - Resume at next lower dose
Grade 3 or 4

Coadministration with strong and moderate CYP3A4 inhibitors

• Avoid concomitant use of the strong CYP3A inhibitor ketoconazole
• With concomitant use of strong CYP3A inhibitors other than ketoconazole, in patients with recommended starting doses of 200mg twice daily or 150mg twice daily, reduce the abemaciclib dose to 100mg twice daily
• In patients who have had a dose reduction to 100mg twice daily due to adverse reactions, further reduce the abemaciclib dose to 50mg twice daily
• If a patient taking abemaciclib discontinues a CYP3A inhibitor, increase the abemaciclib dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong inhibitor
• With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the abemaciclib dose in 50mg decrements if necessary
• Avoid grapefruit or grapefruit juice

Abemaciclib is a potent and selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), and most active against Cyclin D1/CDK4 in enzymatic assays. Abemaciclib prevents retinoblastoma protein (Rb) phosphorylation, blocking cell cycle progression from the G1 to the S-phase of cell division, leading to suppression of tumour growth. In oestrogen receptor-positive breast cancer cell lines, sustained target inhibition with abemaciclib prevented rebound of Rb phosphorylation resulting in cell senescence and apoptosis. In vitro, Rb-negative and Rb-depleted cancer cell lines are generally less sensitive to abemaciclib. In breast cancer xenograft models, abemaciclib dosed daily without interruption at clinically relevant concentrations alone or in combination with anti-oestrogens resulted in reduction of tumour size.

Tablet 50mg

• Yulareb (Eli Lilly) (originator) 

Tablet 100mg

• Yulareb (Eli Lilly) (originator) 

Tablet 150mg

• Yulareb (Eli Lilly) (originator) 

Tablet 200mg

• Yulareb (Eli Lilly) (originator)